因此,研究人员合成了一系列包含不同长度linker的共价分子。通过TR-FRET实验测得Ki和Kinact。Kinact/Ki是用来评估共价键形成速率最准确的一个参数,提供了比IC50更可靠的衡量标准。数据表明:12号化合物,linker长度包含4个碳原子的小分子共价反应速率最快。 经过上述对弹头亲...
结合常数Ki,用koff/kon测量,对应于抑制剂支架的可逆结合,而kinact是激酶和抑制剂之间形成共价键的动力学速率常数。因此,通过 kinact/Ki测量的结合常数KI用于正确描述共价抑制剂的效力。这种共价抑制 (KI) 的动力学常数说明了第一个可逆步骤 (Ki) 的效力和共价键形成的最大潜在速率 (kinact)。 图2.“不可逆共价”...
In addition, the TDI kinetic parameters, the maximal inactivation rate (kinact), the concentration at half kinact (KI), and the kinact/KI ratio, are typically used for risk evaluation. 3.How to Minimize TDI? Many tactics exist in the literature to attenuate TDI via drug design.[4,5]They ...
It describes in detail the raw experimental data that were used to generate the list of Ki and kinact values specifically for the double mutant EGFR-L858R/T790M enzyme. The document also provides links to all theoretical model description files utilized within the DynaFit software package to ...
Owing to their covalent target occupancy, irreversible inhibitors require low exposures and offer long duration, and their use thus represents a powerful strategy for achieving pharmacological efficacy. Importantly, the potency metric of irreversible inhibitors is kinact/KI not IC50. A simple approach to...
IC50 values are often employed as descriptors of enzyme inhibition and inhibitor selectivity, but can be misleading in the study of time-dependent, covalent inhibitors. Due to this disconnect, the second-order rate constant, kinact/KI, is a more appropriate metric of covalent-inhibitor potency. ...
In this system, the kinact/KI value of the test compound is equal to (kinact/KI)probe脳[probe]/IC50. The advantages of this method include simplicity, high throughput, and application to all target classes, and it only requires an in-depth kinetic evaluation of the probe.doi:10.1002/anie....
默克的异恶唑22是mGluR2的强效正变构调节剂,也是CYP3A4的强效TDI(Ki = 540 nM,kinact = 0.064 min–1)。这是一个很大的缺点,特别是由于22的氧化代谢主要由人肝微粒体中的CYP3A4酶介导。因此,默克认为临床DDI可能性较高,并中止了异恶唑22的进一步进展。
The two-time point IC50 shift experiment proved to be an excellent method for the selection of appropriate KI/kinact assay parameters and is suitable for the routine analysis of P450 inhibition by drug candidates.XenobioticaPerloff ES, Mason AK, Dehal SS, Blanchard AP, Morgan L, Ho T, ...
默克的异恶唑22是mGluR2的强效正变构调节剂,也是CYP3A4的强效TDI(Ki = 540 nM,kinact = 0.064 min–1)。这是一个很大的缺点,特别是由于22的氧化代谢主要由人肝微粒体中的CYP3A4酶介导。因此,默克认为临床DDI可能性较高,并中止了异恶唑22的进一步进展。